Nucleosides and their phosphorylated derivatives, nucleotides, are the constituents of DNA or RNA, as well as being biological signaling molecules as is GDP. Nucleoside analogues with modifications at the carbohydrate or base portion have been used extensively as antibiotics and as biological probes. Suhadolnik, Nucleoside Antibiotics, J. Wiley, New York, (1970); Suhadolnik, Nucleoside as Biological Probes, J. Wiley, New York, (1979); Nucleoside Analogues; Chemistry biology and Medicinal Applications, Walk et al., eds., NATO Advanced Study Institute Series: Plenum, New York, Vol. 26, (1979); Thiers, Dermatologic Clinics, 8:583-587 (1990); O'Brien et al., Drugs, 37:233-309 (1989); Shimada et al., 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract 1008, Los Angeles, Calif. (1988); Norbeck et al., Tetrahedron Lett. 6263 (1989); Ezzel, Natural, 326,430; DeClerq, Trends Pharmacol. Sci., 87:339-45 (1987). For example, several nucleoside analogs and purine and pyrimidine base derivatives such as 2-chloro-2'-deoxyadenosine, dideoxyinosine, dideoxycytidine, dideoxythymidine, dideoxyguanidine, 9 -[(2-hydroxymethoxy)methyl]guanine (acylovir) and 9-(3,4-dihydroxybutyl)guanine and the like have found medical utility in treating various disease states such as hairy cell leukemia, as well as being useful as inhibitors of DNA polymerase enzymes and polynucleotide chain terminating reagents for DNA or RNA sequencing studies.
Nucleosides are traditionally synthesized by chemical methods. Nucleoside Analogues; Chemistry, biology and Medicinal Applications, Walk et al., eds., NATO Advanced Study Institute Series: Plenum, New York, Vol. 26, (1979). Enzymatic synthesis of nucleosides based on nucleoside phosphorylase or deoxyribosyl transferase has recently been developed. Krenitsky et al., J. Med. Chem., 29:138-143 (1986); Utagawa et al., Agric. Biol. Chem., 49:3239 (1985); Krenitsky et al., Carbohydr. Res., 97:139-146 (1981); Krenitsky et al., Biochemistry, 20:3615-3621 (1981); Hennen et al., J. Org. Chem., 54:4692 (1989); Betbeder et al., Nucleosides and Nucleotides, 10:465-468 (1991); Hutchinson, TIBTECH, 8:348 (1990).
one of the drawbacks in use of such compounds is in the synthesis of the purine or pyrimidine group linked various sugar rings (furanoses). Thus, although nature prepares each of the furanose derivatives, only ribosyl and 2-deoxyribosyl furanoses are naturally found bonded to nucleic acid bases as nucleosides. In addition, all of the naturally occurring nucleosides and nucleotides contain a purine or pyrimidine nitrogen atom bonded directly to the 1-position of the ribosyl or 2-deoxyribosyl ring; i.e., adjacent to the ring oxygen atom.
It would therefore be beneficial if synthetic routes were available to prepare purine and pyrimidine derivatives bonded to a furanose having other than a ribosyl or deoxyribosyl ring, and bonded at a position other than adjacent the ring oxygen atom. The disclosure that follows describes such syntheses.